Derivatives of 1,3-diazacyclo-alkene-2



United States Patent O DERIVATIVES OF 1,3-DIAZACYCLO-ALKENE-2 Barry M. Bloom, Jackson Heights, N. Y., assignor to Chas. Pfizer & Co., New York, N. Y., a corporation of Delaware No Drawing. Application October 18, 1956 Serial No. 616,639

Claims. (Cl. 260-288) This invention is concerned with new and highly effec tive therapeutic agents. In particular it is concerned with substituted and unsubstituted 1,2,3,4-tetrahydroquinolyl- 1,3-diazacyclopentene 2, 1,2,3,4-tetrahydroisoquinolyl-1, 3-diazacyclopentene-2 and their pharmaceutically acceptable acid addition salts.

In my copending and concurrently filed patent application Serial No. 616,643 entitled, Therapeutic Compositions, I describe certain therapeutic compositions containing pharmaceutically acceptable acid addition salts of 2-(l-naphthylamino)-1,3-diazacyclopentene-2 and 2- (2'-naphthylamino)-1,3-dia2acyclopentene-2. These compositions are potent regulators of the cardiovascular system having the special property of functioning as pressor amines.

In my copending and concurrently filed patent application Serial No. 616,642 entitled, Naphthylamino-l,3- diazacycloalkene, I describe certain substituted naph thylamino-1,3-diazacyclopentenes and their pharmaceutically acceptable acid addition salts which are useful as regulators of the cardiovascular system having the special property of functioning as hypotensive agents.

The compounds of the present invention are diazacyclopentenes wherein the number two carbon atom of said diazacyclopentenes is attached to the heterocyclic nitrogen atom of a tetrahydroquinolyl or tetrahydroisoquinolyl ring. These compounds are also useful as potent regulators of the cardiovascular system being especially active as hypotensive agents. the compounds described in the patent application entitled, Naphthylamino-l,3-diazacycloalkene, they also possess other useful properties such as adrenolytic and vasodilatory action.

Both substituted and unsubstituted compounds of my invention are found to possess hypotensive activity. The substituents on a substituted hypotensive agent may be divided into classes according to whether they are on the aromatic ring of the tetrahydroquinoline or tetrahydroisoquinoline moieties, the partially reduced ring of these moieties, or the carbon atoms of the diazacyclopentene ring.

The aromatic ring of the tetrahydroquinoline and tetrahydroisoquinoline moieties may be substituted with halogen atoms, that is, chlorine, bromine and iodine, alkoxy and alkyl groups containing up to four carbon atoms and hydroxyl groups. The substituents on a substituted partially reduced ring include alkyl groups containing up to four carbon atoms. The substituents on substituted number four and five carbon atoms of a'diazacyclopentene ring includes alkyl groups containing up to four carbon atoms. I

The following list is illustrative of the compounds within the purview of this invention.

1. 2-( l',2',3f,4'-tetrahydro-1-quinolyl) -1,3-diazacyclo' pentene-Z.

In common with I 2. 2-(1',2,3', '-tetrahydro-2'-n-butyl- '-quinolyl) -1,3- diazacyclopentene-2.

3. 2-( l',2',3',4'-tetrahydro-6',7 diethoxy-1-quinolyl)- 1,3-diazacyclopentene-2.

4. 2-(1',2',3',4' tetrahydro 6',7' dihydroxy-1'-quinolyl)-1,B-diazacyclopentene-Z.

S. 2-( 1',2',3',4'-tetrahydro-6'-n-propyl-1-quinolyl) -l,3- diazacyclopentene-2.

6. 2-( l',2',3',4' tetrahydro-2-methyl-1-quinolyl) -4,$- di-n-propyl-l,3-diazacyclopentene-2.

7. 2-( l',2,3',4-tetrahydro 6',7'-dibromo-1'-quinolyl)- 4(or 5) isopropyl-1,3-diazacyclopentene-2.

8. 2 (1,2',3,4' tetrahydro 5' chloro l quinolyl) 4, 5, dimethyl 1, 3 diazacyclopentene 2.

9. 2 (1',2,3',4 tetrahydro 2' isoquinolyl) 1,3- diazacyclopentene-2.

10. 2 (1,2,3',4 tetrahydro 1' methyl 2' isoquinolyl-1,3-diazacyclopentene-2.

11. 2 (1',2',3',4' tetrahydro 3 ethyl 2' isoquinolyl)-4(or 5)ethyl-1,3-diazacyclopentene-2.

12. 2 (1',2',3',4' tetrahydro 6',7' di n butyl 2'- isoquinolyl) 4,5 di n butyl 1,3 diazacyclopentene-2.

13. 2 (1',2',3,4' tetrahydro 3',4 diethyl 2 isoquinolyl) 4,5 diethyl 1,3 diazacyclopentene 2.

14. 2 (1',2',3',4 tetrahydro 8' bromo 2 isoquinolyl) 4(or 5)methyl 1, 3 diazacyclopentene 2.

l5. 2 (1,2,3',4' tetrahydro 5 methoxy 2 isoquinolyl) 1,3 diazacyclopentene 2.

16. 2 (l',2',3',4 tetrahydro 6' hydroxy 2' isoquinolyl) 1,3 diazacyclopentene 2.

The compounds of my invention are best prepared by the method described in my copending and concurrently filed patent application Serial No. 616,640 entitled, Synthesis of 1,3-diazacycloalkene-2. In that application I described the synthesis of 1,3-diazacycloalkene-2 by the reaction between an isothiouronium salt and a diaminoalkane. An isothiouronium salt is prepared for example, by the reaction between an alkyl or an aralkyl halide or sulfate and an N-naphthyl substituted thiourea. For pur-. poses of the present invention the isothiouronium salt is prepared by the reaction between an alkyl or aralkyl halide or sulfate and an N-thiocarbamido-l,2,3,4-tetrahydroquinoline or N-thiocarbamido-1,2,3,4-tetrahydroisoquinoline, the quinolyl and isoquinolyl rings being substituted or unsubstituted in conformance with the description given above.

The synthesis applied to an isoquinolyl compound of the present invention is illustrated below.

For the preparation of a quinolyl compound the iso' quinolyl isothiouronium salt of the above equation would be replaced with a quinolyl isothiouronium salt.

By reference to the above equation it can be seen that the size of the alltyl or aralkyl group, here represented by R, in the' halide" or sulfate used to form theis'o thiouronium salt is of no consequence as far as the final structure of the active compounds of my invention is concerned since it is ultimately removed in the form of a mercaptan. It is, however, convenient to use low molecular weight alkyl halides or sulfates such as methyl iodide or dimethyl sulfate since" the mercapta'newhich are ultimately formed from these types of compounds are relatively volatile and easily removed.

The symbol X in the above equation refers to a chloride, bromide, iodine or sulfate ion'whi'ch together with the active cation forms a pharmaceuticallyacceptable acid addition salt; Other pharmaceuticall'y" acceptable acid addition salts such as,;for example}; suceinate. inaleate, tart'rate, citrate and glycolatec'an' be formed from the halides or sulfates. They can be formed, for example, by converting the halide or sulfate to the free base and treating" thc freebase; with the chosen acid in aqueous solution. Other methods of obtaining these valuable pharmaceutically acceptable acid addition salts are known to those skilled in the art.

The diaminoalkanes of this invention are opened chain diaminoalkanes such as 1,2-diaminoethane and alkyl substituted derivatives wherein the alkyl group and/or groups which replace the hydrogen and/or hydrogens on a carbon atom is an alkyl group containing up'to four carbon atoms.

The acid addition salt which is obtained by carrying out the reactions illustrated in the equations given above is converted to the free base by dissolving it in water and neutralizing the acid with a suitable alkaline reagent such as sodium carbonate. The base can be" isolated from the water by extraction with an immiscible organic solvent preferably one of low volatility such as methylene chloride or benzene.

More specific directions for the preparation of these valuable compounds can be obtained by reference to the appended examples or by reference to the aforesaid patent application, Synthesis of 1,3-diazacycloalkene-2.

The compounds of this invention may be administered alone but are generally administered as a composition with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such excipients as starch, milk sugar, certain types of clay, etc. They may be administered in capsules either alone or in admixture with the" same or equivalent excipients. They may also be administered orally in the form of elixirs or oral suspensions which may contain flavoring or coloring agents. They may be injected parenterally, that is, for example, intramuscularly or subcutaneously. For parenteral administration they are best used in the form of a sterile aqueous solution which may contain other solutes, for example, enough saline or glucose to make the solution isotonic.

The physician will determine the dosage which will be most suitable for an individual patient and it will vary with the form of administration, the age, weight and response of the particular patient. Dosage units containing from 0.1 mg. to 100 mg. are useful. Those dosage unit forms which are prepared for subcutaneous administration will usually contain the lowest concentration of the active ingredient. Dosage forms for intramuscular administration will be somewhat higher and those dosage forms intended for oral administration, for example, elixirs, tablets or capsules will contain still more of the active ingredient.

As might be expected certain of these compounds are more active than others. For example, better activity is found if alkyl groups which are present are no larger than ethyl or a combination of methyl and ethyl groups with the majority of them being methyl groups. With alkoxy groups activity is 'better if there are no" more than two carbon atoms attached to the oxygen. It is better to have no more than two hydroxyl group on a quinolyl or isoquinolyl group and the preferred halogen substituents are chlorine and bromine with no more than three chlorine atoms or two bromine atoms on any given compound.

As noted above the compositions of this invention may take a variety of forms. Various diluents may be employed and the percentage of active ingredient may be varied. It is necessary that the active ingredient constitute a proportion of the composition such that a suitable dosage form will be obtained. Obviously several dosage unit forms may be administered at about the same time. Although compositions with less than 0.05% by weight of active ingredients are suitable, it is preferred to use compositions containing at least 0.05% oi? the active agent. Activityincreases with the concentration of the active agent. The percentage by weight of active agent may be 10, 50, 75, of evenhigher. Dosage unit forms may be prepared with a minor proportion of a carrier and a major proportion of active materials.

The following. examples are given solely for the purpose of illustration and are not to be construed as'limitations of this invention, many variations of which are possible without departing from the spirit or s'cop'e'thereo'f.

N-thiocarbamido-l,2, 3,4-tetrahydroquinoline (50 g.) and 20 ml. of methyl iodide are refluxed in 200ml. of methanol for one hour. The solutioniscooled and most ofthe solvent removed in vacuo to give a heavy precipitate of the isothiouronium hydriodide (M. P. 152.4 to 154.2 C.) which is recovered by filtration. The salt is taken up in an equimolar methanol solution of 1,2-diaminoethane and heated under reflux for ten hours. The solvent" is partially removed in vacuo and the hydriodide salt recovered by filtration; M. P. 194.2 to 196.0 C. 7

Analysis for C H N I:

Calculated Found Carbom- Hydrogem N itrrwen 1 IOdiH8' -c'; 38.

? a or loosens The free base is obtained by treating an'aqueous solution of the hydriodide'with aqueous potassium carbonate, extracting the'aqueo'us solution with methylene chloride and removing the organic solvent in vacuo.

EXAMPLE II Calculated Found Car n 7 4555 Hydrnnan 5. 29, N ltrogen 12. 2

EXAMPLE m 2-(1',2',3',4' tetrahydro-fi,7'-dimeth0xy-2'-is0quinolyl)- 1,3-diazacyclopentene hydrobromide Calculated Found EXAMPLE IV 2-(1',2',3,4-tetrahydr0-2-is0quinolyl) 1,3 diazacyclo pentene-Z N-thiocarbamido-l,2,3,4-tetrahydroisoquinoline (50 g.) and 20 ml. of methyl iodide are refluxed in 200 ml. of methanol for one hour. The solution is cooled and most of the solvent removed in vacuo to give a heavy precipitate of the isothiouronium hydriodide which is recovered by filtration. The salt is taken up in an equimolar methanol solution of 1,2-diaminoethane and heated under reflux for twelve hours. The solvent is partially removed in vacuo and the hydriodide salt recovered by filtration.

The free base is obtained 'by treating an aqueous solution of the hydriodide with aqueous potassium carbonate, extracting the aqueous solution with methylene dichloride and removing the organic solvent in vacuo.

EXAMPLE V 2-(1,2'3',4'-tetrahydro-6'-chloro-I '-quinolyl)-1,3 diaza cycl0pentene-2 N thiocarbamido 6 chloro l,2,3,4 tetrahydroquinoline (50 g.) and 20 ml. of dimethyl sulfate are refluxed in 200 ml. of methanol for one hour. The solution is cooled and most of the solvent removed in vacuo to give a heavy precipitate of the isothiouronium sulfate which is recovered by filtration. The salt is taken up in an equimolar methanol solution of l,2-diaminoethane and heated under reflux for ten hours. Thesolvent is partially removed in vacuo and the sulfate salt recovered by filtration.

The free base is obtained by treating an aqueoussolution of the sulfate with aqueous potassium carbonate, extracting the aqueous solution with methylene dichloride and removing the organic solvent in vacuo.

EXAMPLE VI 2 (1,2',3',4, tetrahydro 6' methoxy 1 quinolyl)- 1,3-diazacyclopentene-2 N thiocarbamido 6 methoxy 1,2,3,4 tetrahydroquinoline (50 g.) and 20 ml. of benzyl bromide are refluxed in 200 ml. of methanol for one hour. The solution is cooled and most of the solvent removed in vacuo to give a heavy precipitate of the isothiouronium hydrobromide which is recovered by filtration. The salt is taken up in an equimolar methanol solution of 1,2-diaminoethane and heated under reflux for twelve hours. The solvent is partially removed in vacuo and the hydrobromide salt recovered by filtration.

The free base is obtained by treating an aqueous solution of the hydrobrornide with aqueous potassium carbonate, extracting the aqueous solution with methylene dichloride and removing the organic solvent in vacuo.

EXAMPLE VII 2 (I ',2',3',4' tetrahydro 6' chloro 2 isoqux'nolyD- 1,3-diazacyclopentene-2 N thiocarbamido 6 chloro 1,2,3,4 tetrahydroisoquinoline (50 g.) and 20 ml. of methyl iodide are refluxed in 200 ml. of methanol for one hour. The solution is cooled and most of the solvent removed in vacuo to give a heavy precipitate of the isothiouronium hydriodide which is recovered by filtration. The salt is taken up in an equimolar methanol solution of 1,2-diaminoethane and heated under reflux for twelve hours. The solvent is partially removed in vacuo and the hydriodide salt recovered by filtration.

The free base is obtained by treating an aqueous solution of the hydriodide with aqueous potassium carbonate, extracting the aqueous solution with methylene dichloride and removing the organic solvent in vacuo.

EXAMPLE VIII 2 (1',2,3',4 tetrahydro 6' methoxy 2' isoquinolyl) -1,3-diazacycl0pentene-2 N thiocarbamido 6 methoxy 1,2,3,4 tetrahydroisoquinoline (50 g.) and 20 ml. of methyl iodide are refiuxed in 200 ml. of methanol for one hour. The solution is cooled and most of the solvent removed in vacuo to give a heavy precipitate of the isothiouronium hydriodide which is recovered by filtration. The salt is taken up in an equimolar methanol solution of 1,2-diaminoethane and heated under reflux for twelve hours. The solvent is partially removed in vacuo and the hydriodide salt recovered by filtration.

The free base is obtained by treating an aqueous solution of the hydriodide with aqueous potassium carbonate, extracting the aqueous solution with methylene di chloride and removing the organic solvent in vacuo.

EXAMPLE IX 2-(] ,2',3,4'-tetrahya'ro-6',7-diethyl-I '-quinolyl) 1,3-diazacyclopentene-2 N-thiocarbamido-6,7-diethyl-l,2,3,4 tetrahydroquinoline (50 g.) and 20 ml. of methyl iodide are refluxed in 200 ml. of methanol for one hour. The solution is cooled and most of the solvent removed in vacuo to give a heavy precipitate of the isothiouronium hydriodide which is recovered by filtration. The salt is taken up in an equimolar methanol solution of 1,2-diaminoethane and heated under reflux for eight hours. The solvent is partially removed in vacuo and the hydriodide salt recovered by filtration.

The free base is obtained by treating an aqueous solution of the hydriodide with aqueous potassium carbonate, extracting the aqueous solution with methylene chloride and removing the organic solvent in vacuo.

EXAMPLE X 2-(] ,2',3',4'-tetrahydro-5',8-dibromo-1-quinolyl) 1,3-diazacyclopentene-2 N-thiocarbamido 5,8 dibromo 1,2,3,4 tetrahydroquinoline (50 g.) and 20 ml. of methyl iodide are refluxed in 200 ml. of methanol for one hour. The solution is cooled and most of the solvent removed in vacuo to give a heavy precipitate of the isothiouronium hydriodide which is recovered by filtration. The salt is taken up in an equimolar methanol solution of 1,2- diaminoethane and heated under reflux for ten hours. The solvent is partially removed in vacuo and the hydriodide salt recovered by filtration.

The free base is obtained by treating an aqueous solution of the hydriodide with aqueous potassium carbonate, extracting the aqueous solution with methylene chloride and removing the organic solvent in vacuo.

7 EXAMPLE XI 1,3-diazacyclopentne-2 N'-thiocarbamido'-6,7-dichloro 1,2 ,3 ,4 tetrahydroisoquinoline (50 g.) and 20 ml. of methyl iodide are refluxed in 200 ml. of methanol for one hour. The solutron is cooled and most of the solvent removed in vacuo togive a heavy precipitate of the isothiouronium hydriojdide which is recovered by filtration. The salt is taltenup in an equimolar methanol solution of 1,2- diaminoethane and heated under reflux for ten hours. The solvent is partially removed in vacuo and thehydriodide salt recovered by filtration.

The free base is obtained by treating an aqueous solution of the hydriodide with aqueouspotassium-carbonate, extracting. the aqueous solution with methylene chloride and removing the organic solvent in vacuo.

EXAMPLE 2'-(I ',2',3',4-tetrdhydr0'quinolylj-4,5-diethyl 1,3-diazacyclpentene-2 hydrochloride N-thiocarbarnido-l,2,3,4,-tetrahydroquinoline (50 g.) and 20 ml. of benzyl chloride are refluxed in 200 ml. of methanol for one hour. The solution is cooled and most of the solvent removed in vacuo to give a heavy precipitate of the isothiouronium hydrochloride which is recovered by filtration. The salt is taken up in an equimolar methanol solution of 3,4-diaminohexane and heated under reflux for twelve hours. The solvent is partially removed in vacuo and the hydrochloride salt recovered by filtration.

EXAMPLE XIII 2-(1 ,2',3 ,4'-tetrahydro-2,3 '-dimeth yl-1 "-quin0lyl) 1,3-diazacycl0pentene-2 hydriodide N-thiocarbamido 2,3 dimethyl 1,2,3,4 tetrahydroquinoline (50 g.) and 20 ml. of methyl iodide are refluxed in 200 ml. of methanol for one hour. The solutron is cooled and most of the solvent removed in vacuo to give a heavy precipitate of the i'sothio'uroniurn hydriodide which is recovered by filtration. The salt is taken up in an equimolarmethanol solution of 1,2- diaminoethane and heated under reflux for ten hours. The solvent is partially removed in vacuo and the hydriodide salt recovered by filtration.

EXAMPLE XIV 2 -(1",2',3',4'-tetrahydro-3' ethyl-y-isoquinolyI) 1,3-diazacyclopentene-2 hydrobromide N-thiocarbamido3-ethyl l,2',3,4 tetrahydrois'oquino line (50 g.) and 20 ml. of n-butyl bromide are refluxed in 200 ml. of methanol for one hour. The solution is cooled and most of the solvent removed in vacuo to give a heavy precipitate of the isothiouronium hydrobromide which is recovered by filtration. The salt is taken up in an equimolar methanol solution of 1,2-diaminoethane and heated under reflux for ten hours. The solvent is partially removed invacuo and the hydrobromide salt recovered by filtration.

EXAMPLE XV 2-(1 ',2',3,4f-tetrahydro-2'-quin0lyl) -4 (0r 5 )-pr0pyl- 1,3-diazacyclopentene-2 hydriodide ta'ining 7.6 g. of glycolic acid. The layers are separated and the glycolic acid salt of 2-(1,2,3',4'-tetrahydro-1- quinolyl)-1,3-diazacyclopentene-2 is recovered from the aqueous layer by evaporation of the solvent in vacuo.

Other pharmaceutically acceptable acid addition salts are prepared from the free bases of this invention in a similar manner.

EXAMPLE XVII A tablet ba seis prepared by blending the following ingredients inthe proportion by weight indicated.

Sucrose, U. S. P. 82.0 Tapioca starch 13.6 Magnesium stearate 4.4

Sucrose, U. S. P 80.3 Tapioca starch 13.2 Magnesium stearate 6.5

Into this base there is blended a sufficient amount of 2-(1-',2,3',4- tetrahydro-6-methoxy-1'-quinolyl)-1,3-diaza cyclopentene-Z to provide tablets each containing 75 mg. of active ingredient.

EXAMPLE XX Into the tablet base of Example XIX there is blended a sufficient amount ofthe hydrobromide salt of 2-(1,2,3', 4'- tetrahydro 6- chloro 2- isoquinolyl)-1,3-diazacyclo pentene-Z to provide tablets each containing-0.1 mg. of active ingredient.

EXAMPLE XXI Ten liters of distilled water for injection, U. S. P. are poured into a 20 l. pyrex glass bottle. To this water is added sufiicient 2-(l,2',3,4-tetrahydro 6- methoxy-2'- isoquino1yl)-1,3 diazacyc1opentene-2 hydrobromide to provide a 0.1 percent'solution by weight.

EXAMPLE XXII A blend is prepared containing the following ingredients:

Grams Calcium carbonate, U. S. P 17.60 Dicalcium sulfate 18.80 Magnesium trisilicate, U. S. P 5.20 Lactose, U. S. P 5.20 Potato starch 5.20 2-(1,2,3,4-tetrahydro-1' quiriolyD-1,3-diazacyclopente'ne-Z 4.00 Magnesium' stearatc A 0.80 Magnesium stearate B 0.32

'This blendis divided and formed into tablets each con- -tai'ning 5 mg. of activeingredient.

9 What is claimed is: 1. A compound selected from the group consisting of 10 2. 2 (1',2',3,4'- tetrahydro-1'-quinoIy1)-1,3-diazacyclopentene-Z.

3. 2-(1,2,3',4- tetrahydro-2'-isoquino1yl) 1,3 diazacyclopentene-Z.

4. 2-(1',2,3',4-tetrahydro-ch1oro-2-isoquino1y1)- 1, diazacyclopentene-Z.

6. 2-(1,2,3,4-tetrahydro-alkoxy-2'-isoquinoly1)-1,3-diazacyc1opentene-2 wherein the alkoxy group contains up to four carbon atoms.

7. 2-(1,2,3,4-tetrahydro-6'-methoxy 2'- isoquinolyD- 1,3-diazacyc1opentene-2.

8. 2-(1',2',3,4-tetrahydro-6',7'-dimethoxy-2'-isoquino1- 1)-1,3-diazacyclopentene-2.

9. 2-(1',2',3',4-tetrahydro-bromo 2'- isoquino1yl)-1,3- diazacyclopentene-Z.

10. 2-(1',2',3,4'-tetrahydro-iodo 2'- isoquinoiyl) 1,3- diazacyclopentene-Z.

References Cited in the file of this patent Richters Organic Chemistry, volume IV, pp. 4-7 (1947).

Urech et al.: Helvetica Chimica Acta, vol 33, No. 182, pp. 1386-4407 

1. A COMPOUND SELECTED FROM THE CONSISTING OF 